Role of fibrillin-1 in protecting against osteoarthritis.

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ImportanceOsteoarthritis is the most common form of arthritis in the UK. It causes joints to become painful and stiff and although symptoms can be mild for some people, for others the pain and mobility issues prevent everyday activities. In the UK osteoarthritis in the knee alone affects 18% of people aged over 45 years. The proportion of the UK population in this age group is growing, and it is predicted that that UK care costs for arthritic conditions will grow to £120 billion per year by 2030. Osteoarthritis is a degenerative condition - one which gets worse over time - and there is currently no drug that can slow or stop osteoarthritis from getting worse.Our goalsThe protein fibrillin-1 (FBN1) is a key component of the network that forms the structure of tissues such as ligaments and bones. We recently discovered that FBN1 may play an important role in osteoarthritis. In addition to other groups' findings that FBN1 levels change in human osteoarthritis, we also found that mice with an abnormal FBN1 protein had early onset osteoarthritis, which was particularly severe in male mice. These findings support a sex-dependent role for FBN1 in osteoarthritis, with FBN1 being critical for avoiding joint failure. In this project we aim to - Define whether loss of FBN1 makes osteoarthritis get worse once it has been triggered or makes joints more susceptible to initial damage in the first place. - Determine the mechanism by which FBN1 causes osteoarthritis. - Test whether preventing FBN1 from breaking down can protect joints from worsening osteoarthritis.Our approachWe have created a team with the range of skills needed to fully understand the role of FBN1 in osteoarthritis, including expertise in the biology of osteoarthritis progression, ligament biology and strength measurements in humans and animals using a mixed engineering and biological approach, creating and using mouse models to understand osteoarthritis and protein breakdown. We will generate mouse strains where FBN1 is deleted in whole limbs or just part of the joint, and also with a variant of FBN1 that is more difficult to break down than the usual form. The mice will be analysed over several months looking at their walking gait, general behaviour, and images of their joints to understand how lack of FBN1/lack of FBN1 breakdown affects joint health and function. We will also use human samples to investigate the mechanism of FBN1 action at a cellular level. ImpactTogether, our experiments will: - determine whether FBN1 controls progression of osteoarthritis only, or whether it also plays a role in initiation. This information is important to determine the timing for treatment targeting FBN1. - unravel the mechanisms by which FBN1 loss accelerates osteoarthritis, and therefore reveal potential targets for therapy. - discover whether preventing FBN1 from breaking down is a valid potential strategy for slowing progression of osteoarthritis.Our work will deliver new scientific insights into the role of FBN1 in osteoarthritis. This paves the way for future work developing new therapies against this increasingly important disease.